Cancer cell - Fibroblast crosstalk via HB-EGF, EGFR, and MAPK signaling promotes the expression of macrophage chemo-attractants in squamous cell carcinoma

Giovanni Giangreco; Antonio Rullan; Yutaka Naito; Dhruva Biswas; Yun-Hsin Liu; Steven Hooper; Pablo Nenclares; Shreerang Bhide; Maggie Chon U Cheang; Probir Chakravarty; Eishu Hirata; Charles Swanton; Alan Melcher; Kevin Harrington; Erik Sahai

doi:10.1016/j.isci.2024.110635

Cancer cell - Fibroblast crosstalk via HB-EGF, EGFR, and MAPK signaling promotes the expression of macrophage chemo-attractants in squamous cell carcinoma

iScience. 2024 Aug 3;27(9):110635. doi: 10.1016/j.isci.2024.110635. eCollection 2024 Sep 20.

Authors

Giovanni Giangreco¹, Antonio Rullan^{1

2

3}, Yutaka Naito¹, Dhruva Biswas^{4

5

6}, Yun-Hsin Liu⁷, Steven Hooper¹, Pablo Nenclares^{2

3}, Shreerang Bhide^{2

3}, Maggie Chon U Cheang^{2

3}, Probir Chakravarty⁷, Eishu Hirata¹, Charles Swanton^{5

6

8}, Alan Melcher^{2

3}, Kevin Harrington^{2

3}, Erik Sahai¹

Affiliations

¹ Tumour Cell Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
² Department of Radiotherapy and Imaging, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
³ Head and Neck Unit, The Royal Marsden Hospital, 203 Fulham Road, London SW3 6JJ, UK.
⁴ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, 72 Huntley Street, London WC1E 6DD, UK.
⁵ Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
⁶ Bill Lyons Informatics Centre, University College London Cancer Institute, 72 Huntley Street, London WC1E 6DD, UK.
⁷ Bioinformatics Platform, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
⁸ Department of Oncology, University College London Hospitals, London, UK.

Abstract

Interactions between cells in the tumor microenvironment (TME) shape cancer progression and patient prognosis. To gain insights into how the TME influences cancer outcomes, we derive gene expression signatures indicative of signaling between stromal fibroblasts and cancer cells, and demonstrate their prognostic significance in multiple and independent squamous cell carcinoma cohorts. By leveraging information within the signatures, we discover that the HB-EGF/EGFR/MAPK axis represents a hub of tumor-stroma crosstalk, promoting the expression of CSF2 and LIF and favoring the recruitment of macrophages. Together, these analyses demonstrate the utility of our approach for interrogating the extent and consequences of TME crosstalk.

Keywords: Cancer; Microenvironment; Transcriptomics.