Distinct molecular profiles and shared drug vulnerabilities in pancreatic metastases of renal cell carcinoma
Clear-cell renal cell carcinoma (ccRCC) is the most common origin of pancreatic metastases (PM). Distinct genomic aberrations, favorable prognosis, and clinical observations on high angiogenesis, and succeeding tyrosine kinase inhibitor (TKI) sensitivity have been reported in PM-ccRCC. However, no functional or single-cell studies have been conducted thus far. We recruited five PM-ccRCC patients and investigated the genomic, single-cell transcriptomic, and drug sensitivity profiles of their patient-derived cells (PDCs). The PM depicted both expected and novel genomic alterations. Further, the transcriptomics differed from both primary and metastatic ccRCC, with upregulations of the PI3K/mTOR and - supporting the clinical observations - angiogenesis pathways. Data integration at pathway level showed that transcriptomics explained drug sensitivities the best. Accordingly, PM-ccRCC PDCs shared sensitivity to many PI3K/mTOR inhibitors. Altogether, we show distinct genomic and transcriptomic signatures in PM-ccRCC, highlight the superiority of transcriptomics in interpreting drug sensitivities, and encourage the use of TKIs and PI3K/mTOR inhibitors in PM-ccRCC.
Authors
- Minttu Polso (ORCID: https://orcid.org/0009-0007-2029-9707)
- Tamara J. Luck (ORCID: https://orcid.org/0000-0002-9859-1261)
- Katja Välimäki (ORCID: https://orcid.org/0000-0001-9117-7589)
- Minna Malmstedt
- Kari K. Alitalo (ORCID: https://orcid.org/0000-0002-7331-0902)
- Teijo Pellinen (ORCID: https://orcid.org/0000-0001-9652-7373)
- Romika Kumari (ORCID: https://orcid.org/0000-0001-5347-7038)
- Pauliina Kallio (ORCID: https://orcid.org/0000-0001-6374-6203)
- Pauli Puolakkainen (ORCID: https://orcid.org/0000-0003-2489-4371)
- Antti Rannikko (ORCID: https://orcid.org/0000-0002-4261-3484)
- Tuomas Mirtti (ORCID: https://orcid.org/0000-0003-0455-9891)
- Olli Kallioniemi (ORCID: https://orcid.org/0000-0002-3231-0332)
- Hanna Seppänen (ORCID: https://orcid.org/0000-0002-2529-651X)
- Caroline A. Heckman (ORCID: https://orcid.org/0000-0002-4324-8706)
- Harri Mustonen (ORCID: https://orcid.org/0000-0001-5632-6796)
- Vilja Pietiäinen (ORCID: https://orcid.org/0000-0003-3125-2406)
- Pekka Ellonen (ORCID: https://orcid.org/0000-0001-6072-0489)
- Piia Mikkonen
- Matilda Roos-Mattila (ORCID: https://orcid.org/0000-0002-2834-3211)
Institutions
- University of Helsinki (FI)
- Science for Life Laboratory (SE)
- Helsinki University Hospital (FI)
- Wihuri Research Institute (FI)
- Institute for Molecular Medicine Finland (FI)
- Hospital District of Helsinki and Uusimaa (FI)
Publication Details
- Journal
- Communications Biology
- Published
- 2024-10-19
- DOI
- https://doi.org/10.1038/s42003-024-07004-9
- Citations
- 2
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 0.57
Funders
- Suomen Lääketieteen Säätiö
- Finska Läkaresällskapet
- Mary och Georg C. Ehrnrooths Stiftelse
- Suomen Kulttuurirahasto
- Biomedicum Helsinki-säätiö
- Magnus Ehrnroothin Säätiö
- Sigrid Juséliuksen Säätiö
- Syöpäsäätiö
- Biocenter Finland
- Helsinki Institute of Life Science, Helsingin Yliopisto