Universität zu Köln

Yamada, Yosuke ORCID: 0000-0001-7952-2706, Belharazem-Vitacolonnna, Djeda, Bohnenberger, Hanibal, Weiss, Christel, Matsui, Naoko, Kriegsmann, Mark, Kriegsmann, Katharina, Sinn, Peter, Simon-Keller, Katja, Hamilton, Gerhard, Graeter, Thomas, Preissler, Gerhard, Ott, German, Scholch, Sebastian, Nakajima, Naoki, Yoshizawa, Akihiko, Haga, Hironori, Date, Hiroshi, Thomas, Roman K., Petrini, Iacopo ORCID: 0000-0002-7752-6866, Giaccone, Giuseppe, Strobel, Philipp and Marx, Alexander (2022). Pulmonary cancers across different histotypes share hybrid tuft cell/ionocyte-like molecular features and potentially druggable vulnerabilities. Cell Death Dis., 13 (11). LONDON: SPRINGERNATURE. ISSN 2041-4889

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Abstract

Tuft cells are chemosensory epithelial cells in the respiratory tract and several other organs. Recent studies revealed tuft cell-like gene expression signatures in some pulmonary adenocarcinomas, squamous cell carcinomas (SQCC), small cell carcinomas (SCLC), and large cell neuroendocrine carcinomas (LCNEC). Identification of their similarities could inform shared druggable vulnerabilities. Clinicopathological features of tuft cell-like (tcl) subsets in various lung cancer histotypes were studied in two independent tumor cohorts using immunohistochemistry (n = 674 and 70). Findings were confirmed, and additional characteristics were explored using public datasets (RNA seq and immunohistochemical data) (n = 555). Drug susceptibilities of tuft cell-like SCLC cell lines were also investigated. By immunohistochemistry, 10-20% of SCLC and LCNEC, and approximately 2% of SQCC expressed POU2F3, the master regulator of tuft cells. These tuft cell-like tumors exhibited lineage ambiguity as they co-expressed NCAM1, a marker for neuroendocrine differentiation, and KRT5, a marker for squamous differentiation. In addition, tuft cell-like tumors co-expressed BCL2 and KIT, and tuft cell-like SCLC and LCNEC, but not SQCC, also highly expressed MYC. Data from public datasets confirmed these features and revealed that tuft cell-like SCLC and LCNEC co-clustered on hierarchical clustering. Furthermore, only tuft cell-like subsets among pulmonary cancers significantly expressed FOXI1, the master regulator of ionocytes, suggesting their bidirectional but immature differentiation status. Clinically, tuft cell-like SCLC and LCNEC had a similar prognosis. Experimentally, tuft cell-like SCLC cell lines were susceptible to PARP and BCL2 co-inhibition, indicating synergistic effects. Taken together, pulmonary tuft cell-like cancers maintain histotype-related clinicopathologic characteristics despite overlapping unique molecular features. From a therapeutic perspective, identification of tuft cell-like LCNECs might be crucial given their close kinship with tuft cell-like SCLC.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Yamada, Yosuke UNSPECIFIED orcid.org/0000-0001-7952-2706 UNSPECIFIED Belharazem-Vitacolonnna, Djeda UNSPECIFIED UNSPECIFIED UNSPECIFIED Bohnenberger, Hanibal UNSPECIFIED UNSPECIFIED UNSPECIFIED Weiss, Christel UNSPECIFIED UNSPECIFIED UNSPECIFIED Matsui, Naoko UNSPECIFIED UNSPECIFIED UNSPECIFIED Kriegsmann, Mark UNSPECIFIED UNSPECIFIED UNSPECIFIED Kriegsmann, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Sinn, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Simon-Keller, Katja UNSPECIFIED UNSPECIFIED UNSPECIFIED Hamilton, Gerhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Graeter, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Preissler, Gerhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Ott, German UNSPECIFIED UNSPECIFIED UNSPECIFIED Scholch, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Nakajima, Naoki UNSPECIFIED UNSPECIFIED UNSPECIFIED Yoshizawa, Akihiko UNSPECIFIED UNSPECIFIED UNSPECIFIED Haga, Hironori UNSPECIFIED UNSPECIFIED UNSPECIFIED Date, Hiroshi UNSPECIFIED UNSPECIFIED UNSPECIFIED Thomas, Roman K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Petrini, Iacopo UNSPECIFIED orcid.org/0000-0002-7752-6866 UNSPECIFIED Giaccone, Giuseppe UNSPECIFIED UNSPECIFIED UNSPECIFIED Strobel, Philipp UNSPECIFIED UNSPECIFIED UNSPECIFIED Marx, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-694293
DOI:	10.1038/s41419-022-05428-x
Journal or Publication Title:	Cell Death Dis.
Volume:	13
Number:	11
Date:	2022
Publisher:	SPRINGERNATURE
Place of Publication:	LONDON
ISSN:	2041-4889
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CELL LUNG-CANCER; NEUROENDOCRINE; SUBTYPES; YAP1; MESOTHELIOMA; CARCINOMA; IMMUNITY; TUMORS Multiple languages Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/69429