Melanoma secretion of transforming growth factor-β2 leads to loss of epidermal AMBRA1 threatening epidermal integrity and facilitating tumour ulceration

I. Cosgarea; A. T. McConnell; T. Ewen; D. Tang; D. S. Hill; M. Anagnostou; M. Elias; R. A. Ellis; A. Murray; L. C. Spender; P. Giglio; M. Gagliardi; A. Greenwood; M. Piacentini; G. J. Inman; G. Fimia; M. Corazzari; J. L. Armstrong; P. E. Lovat

doi:10.1111/bjd.20889

Melanoma secretion of transforming growth factor-β2 leads to loss of epidermal AMBRA1 threatening epidermal integrity and facilitating tumour ulceration

I. Cosgarea, A. T. McConnell, T. Ewen, D. Tang, D. S. Hill, M. Anagnostou, M. Elias, R. A. Ellis, A. Murray, L. C. Spender, P. Giglio, M. Gagliardi, A. Greenwood, M. Piacentini, G. J. Inman, G. Fimia, M. Corazzari, J. L. Armstrong (Lead / Corresponding author), P. E. Lovat

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Abstract

Background: For patients with early American Joint Committee on Cancer (AJCC)-stage melanoma the combined loss of the autophagy regulatory protein AMBRA1 and the terminal differentiation marker loricrin in the peritumoral epidermis is associated with a significantly increased risk of metastasis. Objectives: The aim of the present study was to evaluate the potential contribution of melanoma paracrine transforming growth factor (TGF)-β signalling to the loss of AMBRA1 in the epidermis overlying the primary tumour and disruption of epidermal integrity. Methods: Immunohistochemistry was used to analyse AMBRA1 and TGF-β2 in a cohort of 109 AJCC all-stage melanomas, and TGF-β2 and claudin-1 in a cohort of 30 or 42 AJCC stage I melanomas, respectively, with known AMBRA1 and loricrin (AMLo) expression. Evidence of pre-ulceration was analysed in a cohort of 42 melanomas, with TGF-β2 signalling evaluated in primary keratinocytes. Results: Increased tumoral TGF-β2 was significantly associated with loss of peritumoral AMBRA1 (P < 0·05), ulceration (P < 0·001), AMLo high-risk status (P < 0·05) and metastasis (P < 0·01). TGF-β2 treatment of keratinocytes resulted in downregulation of AMBRA1, loricrin and claudin-1, while knockdown of AMBRA1 was associated with decreased expression of claudin-1 and increased proliferation of keratinocytes (P < 0·05). Importantly, we show loss of AMBRA1 in the peritumoral epidermis was associated with decreased claudin-1 expression (P < 0·05), parakeratosis (P < 0·01) and cleft formation in the dermoepidermal junction (P < 0·05). Conclusions: Collectively, these data suggest a paracrine mechanism whereby TGF-β2 causes loss of AMBRA1 overlying high-risk AJCC early-stage melanomas and reduced epidermal integrity, thereby facilitating erosion of the epidermis and tumour ulceration.

Original language	English
Pages (from-to)	694-704
Number of pages	11
Journal	British Journal of Dermatology
Volume	186
Issue number	4
Early online date	13 Nov 2021
DOIs	https://doi.org/10.1111/bjd.20889
Publication status	Published - 4 Apr 2022

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Cosgarea, I., McConnell, A. T., Ewen, T., Tang, D., Hill, D. S., Anagnostou, M., Elias, M., Ellis, R. A., Murray, A., Spender, L. C., Giglio, P., Gagliardi, M., Greenwood, A., Piacentini, M., Inman, G. J., Fimia, G., Corazzari, M., Armstrong, J. L., & Lovat, P. E. (2022). Melanoma secretion of transforming growth factor-β2 leads to loss of epidermal AMBRA1 threatening epidermal integrity and facilitating tumour ulceration. British Journal of Dermatology, 186(4), 694-704. https://doi.org/10.1111/bjd.20889

@article{21bf7abab6d54540babe042b7317ada4,

title = "Melanoma secretion of transforming growth factor-β2 leads to loss of epidermal AMBRA1 threatening epidermal integrity and facilitating tumour ulceration",

abstract = "Background: For patients with early American Joint Committee on Cancer (AJCC)-stage melanoma the combined loss of the autophagy regulatory protein AMBRA1 and the terminal differentiation marker loricrin in the peritumoral epidermis is associated with a significantly increased risk of metastasis. Objectives: The aim of the present study was to evaluate the potential contribution of melanoma paracrine transforming growth factor (TGF)-β signalling to the loss of AMBRA1 in the epidermis overlying the primary tumour and disruption of epidermal integrity. Methods: Immunohistochemistry was used to analyse AMBRA1 and TGF-β2 in a cohort of 109 AJCC all-stage melanomas, and TGF-β2 and claudin-1 in a cohort of 30 or 42 AJCC stage I melanomas, respectively, with known AMBRA1 and loricrin (AMLo) expression. Evidence of pre-ulceration was analysed in a cohort of 42 melanomas, with TGF-β2 signalling evaluated in primary keratinocytes. Results: Increased tumoral TGF-β2 was significantly associated with loss of peritumoral AMBRA1 (P < 0·05), ulceration (P < 0·001), AMLo high-risk status (P < 0·05) and metastasis (P < 0·01). TGF-β2 treatment of keratinocytes resulted in downregulation of AMBRA1, loricrin and claudin-1, while knockdown of AMBRA1 was associated with decreased expression of claudin-1 and increased proliferation of keratinocytes (P < 0·05). Importantly, we show loss of AMBRA1 in the peritumoral epidermis was associated with decreased claudin-1 expression (P < 0·05), parakeratosis (P < 0·01) and cleft formation in the dermoepidermal junction (P < 0·05). Conclusions: Collectively, these data suggest a paracrine mechanism whereby TGF-β2 causes loss of AMBRA1 overlying high-risk AJCC early-stage melanomas and reduced epidermal integrity, thereby facilitating erosion of the epidermis and tumour ulceration.",

author = "I. Cosgarea and McConnell, {A. T.} and T. Ewen and D. Tang and Hill, {D. S.} and M. Anagnostou and M. Elias and Ellis, {R. A.} and A. Murray and Spender, {L. C.} and P. Giglio and M. Gagliardi and A. Greenwood and M. Piacentini and Inman, {G. J.} and G. Fimia and M. Corazzari and Armstrong, {J. L.} and Lovat, {P. E.}",

note = "Funding - Research in the UK (study design, data collection, data analysis and manuscript preparation) was supported by Melanoma Focus (IC, RAE, ATM, DSH, MA, ME, AG, JLA, by a project grant to RAE and PEL), The North East Skin Research Fund (TE, ME, RAE, PEL), The British Skin Foundation (DT, ATM, RAE, JLA, PEL), The Newcastle Health Care Charity (MA, ATM, DSH RAE and PEL), University of Sunderland Beacon Fund (JLA), Worldwide Cancer Research (LS and GJI, by a project grant (11-078) to GJI), CRUK (GJI) and by a scholarship to IC from the Deutsche Forschungsgemeinschaft (DFG, CO 1931/1-1). Research in Italy (GF, PG, MG, MP and MC; data collection, data analysis and manuscript preparation) was supported by the Assocaizione Italiana per la Ricerca sul Cancro (AIRC, MFAG-11743 to MC), IG2015 n. 17404 to GMF, and IG2018 no. 21880 to MP, and Ricerca Corrente (Italian Ministry of Health to GMF and MP). ",

year = "2022",

month = apr,

day = "4",

doi = "10.1111/bjd.20889",

language = "English",

volume = "186",

pages = "694--704",

journal = "British Journal of Dermatology",

issn = "0007-0963",

publisher = "Wiley",

number = "4",

}

Cosgarea, I, McConnell, AT, Ewen, T, Tang, D, Hill, DS, Anagnostou, M, Elias, M, Ellis, RA, Murray, A, Spender, LC, Giglio, P, Gagliardi, M, Greenwood, A, Piacentini, M, Inman, GJ, Fimia, G, Corazzari, M, Armstrong, JL & Lovat, PE 2022, 'Melanoma secretion of transforming growth factor-β2 leads to loss of epidermal AMBRA1 threatening epidermal integrity and facilitating tumour ulceration', British Journal of Dermatology, vol. 186, no. 4, pp. 694-704. https://doi.org/10.1111/bjd.20889

TY - JOUR

T1 - Melanoma secretion of transforming growth factor-β2 leads to loss of epidermal AMBRA1 threatening epidermal integrity and facilitating tumour ulceration

AU - Cosgarea, I.

AU - McConnell, A. T.

AU - Ewen, T.

AU - Tang, D.

AU - Hill, D. S.

AU - Anagnostou, M.

AU - Elias, M.

AU - Ellis, R. A.

AU - Murray, A.

AU - Spender, L. C.

AU - Giglio, P.

AU - Gagliardi, M.

AU - Greenwood, A.

AU - Piacentini, M.

AU - Inman, G. J.

AU - Fimia, G.

AU - Corazzari, M.

AU - Armstrong, J. L.

AU - Lovat, P. E.

N1 - Funding - Research in the UK (study design, data collection, data analysis and manuscript preparation) was supported by Melanoma Focus (IC, RAE, ATM, DSH, MA, ME, AG, JLA, by a project grant to RAE and PEL), The North East Skin Research Fund (TE, ME, RAE, PEL), The British Skin Foundation (DT, ATM, RAE, JLA, PEL), The Newcastle Health Care Charity (MA, ATM, DSH RAE and PEL), University of Sunderland Beacon Fund (JLA), Worldwide Cancer Research (LS and GJI, by a project grant (11-078) to GJI), CRUK (GJI) and by a scholarship to IC from the Deutsche Forschungsgemeinschaft (DFG, CO 1931/1-1). Research in Italy (GF, PG, MG, MP and MC; data collection, data analysis and manuscript preparation) was supported by the Assocaizione Italiana per la Ricerca sul Cancro (AIRC, MFAG-11743 to MC), IG2015 n. 17404 to GMF, and IG2018 no. 21880 to MP, and Ricerca Corrente (Italian Ministry of Health to GMF and MP).

PY - 2022/4/4

Y1 - 2022/4/4

N2 - Background: For patients with early American Joint Committee on Cancer (AJCC)-stage melanoma the combined loss of the autophagy regulatory protein AMBRA1 and the terminal differentiation marker loricrin in the peritumoral epidermis is associated with a significantly increased risk of metastasis. Objectives: The aim of the present study was to evaluate the potential contribution of melanoma paracrine transforming growth factor (TGF)-β signalling to the loss of AMBRA1 in the epidermis overlying the primary tumour and disruption of epidermal integrity. Methods: Immunohistochemistry was used to analyse AMBRA1 and TGF-β2 in a cohort of 109 AJCC all-stage melanomas, and TGF-β2 and claudin-1 in a cohort of 30 or 42 AJCC stage I melanomas, respectively, with known AMBRA1 and loricrin (AMLo) expression. Evidence of pre-ulceration was analysed in a cohort of 42 melanomas, with TGF-β2 signalling evaluated in primary keratinocytes. Results: Increased tumoral TGF-β2 was significantly associated with loss of peritumoral AMBRA1 (P < 0·05), ulceration (P < 0·001), AMLo high-risk status (P < 0·05) and metastasis (P < 0·01). TGF-β2 treatment of keratinocytes resulted in downregulation of AMBRA1, loricrin and claudin-1, while knockdown of AMBRA1 was associated with decreased expression of claudin-1 and increased proliferation of keratinocytes (P < 0·05). Importantly, we show loss of AMBRA1 in the peritumoral epidermis was associated with decreased claudin-1 expression (P < 0·05), parakeratosis (P < 0·01) and cleft formation in the dermoepidermal junction (P < 0·05). Conclusions: Collectively, these data suggest a paracrine mechanism whereby TGF-β2 causes loss of AMBRA1 overlying high-risk AJCC early-stage melanomas and reduced epidermal integrity, thereby facilitating erosion of the epidermis and tumour ulceration.

AB - Background: For patients with early American Joint Committee on Cancer (AJCC)-stage melanoma the combined loss of the autophagy regulatory protein AMBRA1 and the terminal differentiation marker loricrin in the peritumoral epidermis is associated with a significantly increased risk of metastasis. Objectives: The aim of the present study was to evaluate the potential contribution of melanoma paracrine transforming growth factor (TGF)-β signalling to the loss of AMBRA1 in the epidermis overlying the primary tumour and disruption of epidermal integrity. Methods: Immunohistochemistry was used to analyse AMBRA1 and TGF-β2 in a cohort of 109 AJCC all-stage melanomas, and TGF-β2 and claudin-1 in a cohort of 30 or 42 AJCC stage I melanomas, respectively, with known AMBRA1 and loricrin (AMLo) expression. Evidence of pre-ulceration was analysed in a cohort of 42 melanomas, with TGF-β2 signalling evaluated in primary keratinocytes. Results: Increased tumoral TGF-β2 was significantly associated with loss of peritumoral AMBRA1 (P < 0·05), ulceration (P < 0·001), AMLo high-risk status (P < 0·05) and metastasis (P < 0·01). TGF-β2 treatment of keratinocytes resulted in downregulation of AMBRA1, loricrin and claudin-1, while knockdown of AMBRA1 was associated with decreased expression of claudin-1 and increased proliferation of keratinocytes (P < 0·05). Importantly, we show loss of AMBRA1 in the peritumoral epidermis was associated with decreased claudin-1 expression (P < 0·05), parakeratosis (P < 0·01) and cleft formation in the dermoepidermal junction (P < 0·05). Conclusions: Collectively, these data suggest a paracrine mechanism whereby TGF-β2 causes loss of AMBRA1 overlying high-risk AJCC early-stage melanomas and reduced epidermal integrity, thereby facilitating erosion of the epidermis and tumour ulceration.

UR - http://www.scopus.com/inward/record.url?scp=85122102989&partnerID=8YFLogxK

U2 - 10.1111/bjd.20889

DO - 10.1111/bjd.20889

M3 - Article

C2 - 34773645

SN - 0007-0963

VL - 186

SP - 694

EP - 704

JO - British Journal of Dermatology

JF - British Journal of Dermatology

IS - 4

ER -

Melanoma secretion of transforming growth factor-β2 leads to loss of epidermal AMBRA1 threatening epidermal integrity and facilitating tumour ulceration

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Understanding Resistance to Targeted Therapies in Oesophageal Squamous Cell Carcinoma as a Foundation to Developing New Precision Medicine Approaches

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Melanoma secretion of transforming growth factor-β2 leads to loss of epidermal AMBRA1 threatening epidermal integrity and facilitating tumour ulceration

Abstract

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Understanding Resistance to Targeted Therapies in Oesophageal Squamous Cell Carcinoma as a Foundation to Developing New Precision Medicine Approaches

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