Paracrine behaviors arbitrate parasite-like interactions between tumor subclones

Explaining the emergence and maintenance of intratumour heterogeneity is an important question in cancer biology. Tumour cells can generate considerable subclonal diversity, which influences tumour growth rate, treatment resistance and metastasis, yet we know remarkably little about how cells from different subclones interact. Here, we confronted two murine mammary cancer cell lines to determine both the nature and mechanisms of subclonal cellular interactions in vitro. Surprisingly, we found that compared to monoculture, growth of the ‘winner’ was enhanced by the presence of the ‘loser’ cell line, whereas growth of the latter was reduced. Our assays indicated that these interactions are mediated by the production of paracrine metabolites resulting in the winner subclone effectively ‘farming’ the loser. Our findings add a new level of complexity to the mechanisms underlying the subclonal growth dynamics and suggest that in vivo tumour interactions could be more diverse than previously thought..

Targeted deep sequencing of DNA from multiple tissue types improves the diagnostic rate and reveals a highly diverse phenotype of mosaic neurofibromatosis type 2

BackgroundAlthough 60% of patients with de novo neurofibromatosis type 2 (NF2) are presumed to have mosaic NF2, the actual diagnostic rate of this condition remains low at around 20% because of the existing difficulties in detecting NF2 variants with low variant allele frequency (VAF). Here, we examined the correlation between the genotype and phenotype of mosaic NF2 after improving the diagnostic rate of mosaic NF2.MethodsWe performed targeted deep sequencing of 36 genes including NF2 using DNA samples from multiple tissues (blood, buccal mucosa, hair follicle and tumour) of 53 patients with de novo NF2 and elucidated their genotype–phenotype correlation.ResultsTwenty-four patients (45.2%) had the NF2 germline variant, and 20 patients with NF2 (37.7%) had mosaic NF2. The mosaic NF2 phenotype was significantly different from that in patients with NF2 germline variant in terms of distribution of NF2-related disease, tumour growth rate and hearing outcome. The behaviour of schwannoma correlated to the extent of VAF with NF2 variant in normal tissues unlike meningioma.ConclusionWe have improved the diagnostic rate of mosaic NF2 compared with that of previous studies by targeted deep sequencing of DNA from multiple tissues. Many atypical patients with NF2 diagnosed with ‘unilateral vestibular schwannoma’ or ‘multiple meningiomas’ presumably have mosaic NF2. Finally, we suggest that the highly diverse phenotype of NF2 could result not only from the type and location of NF2 variant but also the extent of VAF in the NF2 variant within normal tissue DNA.

Mathematical deconvolution of CAR T-cell proliferation and exhaustion from real-time killing assay data

Chimeric antigen receptor (CAR) T-cell therapy has shown promise in the treatment of haematological cancers and is currently being investigated for solid tumours, including high-grade glioma brain tumours. There is a desperate need to quantitatively study the factors that contribute to the efficacy of CAR T-cell therapy in solid tumours. In this work, we use a mathematical model of predator–prey dynamics to explore the kinetics of CAR T-cell killing in glioma: the Chimeric Antigen Receptor T-cell treatment Response in GliOma (CARRGO) model. The model includes rates of cancer cell proliferation, CAR T-cell killing, proliferation, exhaustion, and persistence. We use patient-derived and engineered cancer cell lines with an in vitro real-time cell analyser to parametrize the CARRGO model. We observe that CAR T-cell dose correlates inversely with the killing rate and correlates directly with the net rate of proliferation and exhaustion. This suggests that at a lower dose of CAR T-cells, individual T-cells kill more cancer cells but become more exhausted when compared with higher doses. Furthermore, the exhaustion rate was observed to increase significantly with tumour growth rate and was dependent on level of antigen expression. The CARRGO model highlights nonlinear dynamics involved in CAR T-cell therapy and provides novel insights into the kinetics of CAR T-cell killing. The model suggests that CAR T-cell treatment may be tailored to individual tumour characteristics including tumour growth rate and antigen level to maximize therapeutic benefit.

When, why and how clonal diversity predicts future tumour growth

Intratumour heterogeneity holds promise as a prognostic biomarker in multiple cancer types. However, the relationship between this marker and its clinical impact is mediated by an evolutionary process that is not well understood. Here we employ a spatial computational model of tumour evolution to assess when, why and how intratumour heterogeneity can be used to forecast tumour growth rate, an important predictor of clinical progression. We identify three conditions that can lead to a positive correlation between clonal diversity and subsequent growth rate: diversity is measured early in tumour development; selective sweeps are rare; and/or tumours vary in the rate at which they acquire driver mutations. Opposite conditions typically lead to negative correlation. Our results further suggest that prognosis can be better predicted on the basis of both clonal diversity and genomic instability than either factor alone. Nevertheless, we find that, for predicting tumour growth, clonal diversity is likely to perform worse than conventional measures of tumour stage and grade. We thus offer explanations – grounded in evolutionary theory – for empirical findings in various cancers. Our work informs the search for new prognostic biomarkers and contributes to the development of predictive oncology.

Impact of tumour growth rate during preceding treatment on tumour response to regorafenib or trifluridine/tipiracil in refractory metastatic colorectal cancer

BackgroundAlthough regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) have been recognised as standard treatments in metastatic colorectal cancer (mCRC), the best option remains unclear. Pretreatment tumour growth rate (TGR) is associated with radiotherapeutic efficacy in laryngeal cancer. However, no reports are available on the association between TGR during preceding treatment and the efficacy of REG or FTD/TPI.Patients and methodsWe retrospectively analysed the data of consecutive mCRC patients treated with REG or FTD/TPI and classified them into slow-growing or rapid-growing (SG or RG) groups according to TGR and emergence of new lesion (NL+) or their absence (NL−) during preceding treatment period [SG: NL− with low TGR (<0.33%/day); RG: NL+ or high TGR (≥0.33%/day)].ResultsA total of 244 patients (RG/SG, 133/111; REG/FTD/TPI, 132/112) were eligible. The RG proportion with a long duration from first-line chemotherapy and the SG proportion with elevated alkaline phosphatase were higher in REG, whereas the SG proportion with performance status 2 was higher in FTD/TPI. The disease control rates (DCRs) were similar between REG and FTD/TPI (24%/30%; OR: 0.74; p=0.44; adjusted OR: 0.73; p=0.47) in the RG, whereas the DCR was significantly higher for FTD/TPI than for REG (47%/26%; OR: 2.56; p=0.029; adjusted OR: 3.38; p=0.01) in the SG.ConclusionsTGR and NL during preceding treatment may be helpful for drug selection in refractory mCRC patients to be treated with REG or FTD/TPI. However, further studies are needed to confirm the value of TGR for drug selection.