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Loss of AXIN1 Drives Acquired Resistance to WNT Pathway Blockade in Colorectal Cancer Cells Carrying RSPO3 Fusions

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Loss of AXIN1 Drives Acquired Resistance to WNT Pathway Blockade in Colorectal Cancer Cells Carrying RSPO3 Fusions Report Loss of AXIN1 drives acquired resistance to WNT pathway blockade in colorectal cancer cells carrying RSPO3 fusions Gabriele Picco1,2, Consalvo Petti1,2, Alessia Centonze2, Erica Torchiaro1,3, Giovanni Crisafulli1, Luca Novara1, Andrea Acquaviva4, Alberto Bardelli1,2 & Enzo Medico1,2,* Abstract 2014). In a molecular survey carried out by The Cancer Genome Atlas, 93% of CRCs have been found to carry a genetic alteration in In colorectal cancer (CRC), WNT pathway activation by genetic at least one of 16 WNT pathway genes, defining this pathway as a rearrangements of RSPO3 is emerging as a promising target. major driver of CRC (Cancer Genome Atlas, 2012). In particular, However, its low prevalence severely limits availability of preclini- loss of function of the WNT pathway suppressor APC accounts for cal models for in-depth characterization. Using a pipeline designed 70% of all CRCs. APC alterations typically occur at early steps of the to suppress stroma-derived signal, we find that RSPO3 “outlier” colorectal adenoma–carcinoma sequence (Powell et al, 1992; Morin expression in CRC samples highlights translocation and fusion et al, 1997), a typical feature of “trunk” genetic events, present in transcript expression. Outlier search in 151 CRC cell lines identified all cancer cells and therefore therapeutically attractive (Swanton, VACO6 and SNU1411 cells as carriers of, respectively, a canonical 2012). Accordingly, established CRCs were found to critically PTPRK(e1)-RSPO3(e2) fusion and a novel PTPRK(e13)-RSPO3(e2) depend on APC mutation-driven enhanced WNT signaling, even in fusion. Both lines displayed marked in vitro and in vivo sensitivity the presence of additional cancer-driving mutations (Dow et al, to WNT blockade by the porcupine inhibitor LGK974, associated 2015). Genomic rearrangements involving the RSPO2 and RSPO3 with transcriptional and morphological evidence of WNT pathway genes have been found to provide an alternative mechanism of aber- suppression. Long-term treatment of VACO6 cells with LGK974 led rant WNT pathway activation in CRC (Seshagiri et al, 2012). These to the emergence of a resistant population carrying two frameshift genes encode secreted proteins, R-spondins, that synergize with deletions of the WNT pathway inhibitor AXIN1, with consequent WNT ligands to promote b-catenin signaling (de Lau et al, 2011). protein loss. Suppression of AXIN1 in parental VACO6 cells by RNA RSPO2 and RSPO3 translocations are mutually exclusive with APC interference conferred marked resistance to LGK974. These results mutations and lead to aberrant expression of fusion transcripts in provide the first mechanism of secondary resistance to WNT path- which the 50 portion, upstream from the RSPO coding sequence, is way inhibition. typically contributed by the highly expressed EIF3E and PTPRK genes, respectively (Seshagiri et al, 2012). Keywords colorectal cancer; gene fusion; R-spondin; targeted therapy; In the case of the PTPRK-RSPO3 translocation, recent studies in WNT pathway patient-derived xenografts (PDXs) carrying the fusion transcript Subject Categories Cancer; Digestive System; Systems Medicine demonstrated that inhibition of WNT ligand secretion by porcupine DOI 10.15252/emmm.201606773 | Received 4 July 2016 | Revised 18 December blockade, or direct targeting of RSPO3 by antibodies, markedly inhi- 2016 | Accepted 20 December 2016 bits tumor growth, promoting loss of cancer stem cell functions and differentiation (Chartier et al, 2016; Madan et al, 2016; Storm et al, 2016). These results highlight the clinical relevance of targeting RSPO3 rearrangements in CRC patients. As for all pathway-targeted Introduction therapies, availability of experimental models is crucial to character- ize the dependency on pathway activators and to explore possible Most colorectal cancers display aberrant activation of the WNT mechanisms of release from such dependency (Misale et al, 2014; pathway, leading to stabilization and nuclear translocation of Rosa et al, 2014). Indeed, mechanisms of acquired resistance to b-catenin, a key transcriptional regulator controlling stem cell main- WNT pathway inhibition are currently unexplored. In this view, tenance, proliferation, and differentiation (Krausova & Korinek, availability of established CRC cell lines spontaneously carrying 1 Candiolo Cancer Institute – FPO IRCCS, Candiolo, Torino, Italy 2 Department of Oncology, University of Torino, Candiolo, Torino, Italy 3 Istituto Nazionale Biostrutture e Biosistemi - Consorzio Interuniversitario, Roma, Italy 4 Department of Computer and Control Engineering, Politecnico di Torino, Turin, Italy *Corresponding author. Tel: +39 011 9933 234; Fax: +39 011 9933225; E-mail: [email protected] ª 2017 The Authors. Published under the terms of the CC BY 4.0 license EMBO Molecular Medicine 1 EMBO Molecular Medicine RSPO3 translocations in CRC cell lines Gabriele Picco et al RSPO3 fusions would provide a valuable resource. We recently from the RSPO3 expression value and found that in a subset of reported a large collection of 151 CRC cell lines and associated samples, presenting low CAF score values and high RSPO3 expres- global gene expression profiles, reliably representing the molecular sion, this delta value raises to Z-score levels usually observed for heterogeneity of CRC (Medico et al, 2015). We have also shown that outlier genes (Fig 1B). The relationship between RSPO3 levels and expression-based outlier analysis within this compendium leads to CAF score was further validated in an independent 2140-sample identification of therapeutically actionable oncogenic drivers CRC microarray dataset, highlighting the presence of samples with (Medico et al, 2015). Considering that, in RSPO3 rearrangements, a high RSPO3 expression not justified by abundant stroma strong promoter is placed upstream of the RSPO3 coding sequence, (Appendix Fig S2). In principle, RSPO3 fusions are expressed only we hypothesized that searching for outlier RSPO3 expression might by cancer cells; therefore, outlier samples characterized by low CAF pinpoint cases carrying the respective translocation. This hypothesis score should be enriched in fusion transcripts. To test this hypothe- was tested in RNA-seq-based expression data generated by the sis, the 14 RSPO3 overexpressing samples described above were TCGA, checking the presence of the RSPO3 fusion in outlier cases. subdivided in two groups, respectively, having a positive and a Outlier expression analysis was then extended to the 151 CRC cell negative delta (RSPO3-CAF score). Notably, the six RSPO3 fusions lines, leading to the identification of two unique lines carrying a were exclusively present in the positive delta group, also corre- RSPO3 fusion. We employed these cell lines to investigate addiction sponding to delta Z-score values higher than 2.5 (Fig 1B, to WNT pathway activation mediated by PTPRK-RSPO3 trans- Appendix Table S1). To verify whether additional RSPO3 fusions locations, modeling primary sensitivity and acquired secondary were present in samples not identified by the above approach, we resistance. extended the search for RSPO3 fusions to 12 additional TCGA RNA- seq samples expressing lower levels of RSPO3. In particular, for any expression level, we selected samples with the lowest CAF score, so Results and Discussion that at least a fraction of the RSPO3 reads could theoretically derive from epithelial cells (Appendix Fig S3). None of these samples was Identification of RSPO3 rearrangements in CRC samples by found to carry a RSPO3 fusion, suggesting that our approach satu- combined stroma/transcript expression analysis rated the dataset and captured all the samples carrying RSPO3 rear- rangements. Samples with lower levels were not explored because PTPRK-RSPO3 rearrangements typically lead to aberrant expression the limited number of expected RNA-seq reads covering RSPO3 of fusion transcripts by colorectal cancer cells that normally do not would anyway not allow detection of reads covering a fusion express RSPO3 (Sato et al, 2009; Seshagiri et al, 2012). Therefore, transcript. Cross-check with an available pan-cancer database of in principle, searching for CRC samples displaying high RSPO3 fusion transcripts in TCGA samples (http://www.tumorfusions.org; mRNA levels should pinpoint tumors bearing RSPO3 fusions. Yoshihara et al, 2015) revealed that no additional RSPO3 fusions were However, stromal cells have been identified as a source for RSPO3 detected in the 450-sample TCGA dataset used for our analysis. expression in the intestine (Kabiri et al, 2014). To verify the stromal These results show that the presence of RSPO3 rearrangements origin of RSPO3 transcripts in CRC, we exploited the fact that in in CRC can be anticipated by high RSPO3 mRNA levels not justified CRC patient-derived xenografts (PDXs), human stroma is substi- by abundant stroma. tuted by mouse stroma (Isella et al, 2015). Analysis of our previous species-specific analysis of RNA-seq data from CRC PDXs (Isella Transcriptional outlier analysis identifies CRC cell lines carrying et al, 2015) revealed that the fraction of RSPO3 transcripts of mouse canonical and novel PTPRK-RSPO3 rearrangements origin is 99.9%. As a consequence, it is expected that in a human CRC sample, RSPO3 mRNA levels are correlated with the richness To search for established cell lines carrying RSPO3 rearrangements, of stroma that we found to be reliably approximated by a transcrip- we analyzed RSPO3 expression levels in our previously described tional cancer-associated
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