Histone demethylase KDM5D upregulation drives sex differences in colon cancer.

Sex exerts a profound impact on cancer incidence, spectrum and outcomes, yet the molecular and genetic bases of such sex differences are ill-defined and presumptively ascribed to X-chromosome genes and sex hormones1. Such sex differences are particularly prominent in colorectal cancer (CRC) in which men experience higher metastases and mortality. A murine CRC model, engineered with an inducible transgene encoding oncogenic mutant KRASG12D and conditional null alleles of Apc and Trp53 tumour suppressors (designated iKAP)2, revealed higher metastases and worse outcomes specifically in males with oncogenic mutant KRAS (KRAS*) CRC. Integrated cross-species molecular and transcriptomic analyses identified Y-chromosome gene histone demethylase KDM5D as a transcriptionally upregulated gene driven by KRAS*-mediated activation of the STAT4 transcription factor. KDM5D-dependent chromatin mark and transcriptome changes showed repression of regulators of the epithelial cell tight junction and major histocompatibility complex class I complex components. Deletion of Kdm5d in iKAP cancer cells increased tight junction integrity, decreased cell invasiveness and enhanced cancer cell killing by CD8+ T cells. Conversely, iAP mice engineered with a Kdm5d transgene to provide constitutive Kdm5d expression specifically in iAP cancer cells showed an increased propensity for more invasive tumours in vivo. Thus, KRAS*-STAT4-mediated upregulation of Y chromosome KDM5D contributes substantially to the sex differences in KRAS* CRC by means of its disruption of cancer cell adhesion properties and tumour immunity, providing an actionable therapeutic strategy for metastasis risk reduction for men afflicted with KRAS* CRC.

Exploratory study of macrophage polarization and spatial distribution in colorectal cancer liver metastasis: a pilot study.

Background: The liver is the most typical site of metastatic disease for patients with colorectal cancer (CRC), and up to half the patients with CRC will develop colorectal liver metastasis (CLM). Studying the tumor microenvironment, particularly macrophages and their spatial distribution, can give us critical insight into treatment. Methods: Ten CLMs (five treatment-naïve and five post-neoadjuvant chemotherapy) were stained with multiplex immunofluorescence panels against cytokeratins, CD68, Arg1, CD206, CD86, CD163, PD-L1, and MRP8-14. Densities of cell phenotypes and their spatial distribution in the tumor center and the normal liver-tumor interface were correlated with clinicopathological variables. Results: M2 macrophages were the predominant subtype in both the tumor center and the periphery, with a relatively higher density at the periphery. The larger tumors, more than 3.9 cm, were associated with higher densities of total CD68+ macrophages and CD68+CD163+ CD206neg and CD68+CD206+ CD163neg M2 macrophage subtypes. Total macrophages in the tumor periphery demonstrated significantly greater proximity to malignant cells than did those in the tumor center (p=0.0371). The presence of higher than median CD68+MRP8-14+CD86neg M1 macrophages in the tumor center was associated with poor overall survival (median 2.34 years) compared to cases with lower than median M1 macrophages at the tumor center (median 6.41 years) in univariate analysis. Conclusion: The dominant polarization of the M2 macrophage subtype could drive new therapeutic approaches in CLM patients.

TP53 Alteration and Its Effect on Pathologic Response Are Associated with Survival after Resection of Colorectal Liver Metastases.

The aims of this study were to assess the effect of known gene alterations (RAS, TP53, APC, SMAD4, BRAF, and FBXW7) on pathologic response (PR) and their combined association with survival in patients with colorectal liver metastases (CLM). From a prospectively maintained database, we collected data on 458 patients who underwent curative-intent hepatectomy after receiving the first-line preoperative chemotherapy between 2004 and 2020. Major PR was defined as tumor viability of less than 50% in all tumors. Multivariate logistic regression revealed that oxaliplatin-containing regimen (OR: 2.54, 95% CI: 1.58-4.07, P < 0.001), bevacizumab-containing regimen (OR: 2.15, 95%CI: 1.36-3.39, P = 0.001), and TP53 alteration (OR: 0.42, 95%CI: 0.27-0.66, P < 0.001) were independently associated with major PR. Multivariate Cox regression also revealed that patients with TP53 wild-type and major PR (HR: 0.49, 95%CI: 0.31-0.77, P = 0.002) and those with TP53 alteration and major PR (HR: 0.70, 95%CI: 0.49-1.00, P = 0.048) had significantly better overall survival compared to those with minor PR. Further studies targeting the association of TP53 with PR and survival can help clarify the role of TP53 in CLM.

New Insights into Macrophage Polarization and its Prognostic Role in Patients with Colorectal Cancer Liver Metastasis.

Background: As liver metastasis is the most common cause of mortality in patients with colorectal cancer, studying colorectal cancer liver metastasis (CLM) microenvironment is essential for improved understanding of tumor biology and to identify novel therapeutic targets. Methods: We used multiplex immunofluorescence platform to study tumor associated macrophage (TAM) polarization and adaptive T cell subtypes in tumor samples from 105 CLM patients (49 without and 56 with preoperative chemotherapy). Results: CLM exhibited M2 macrophage polarization, and helper T cells were the prevalent adaptive T cell subtype. The density of total, M2 and TGFß-expressing macrophages, and regulatory T cells was lower in CLM treated with preoperative chemotherapy. CLM with right-sided primary demonstrated enrichment of TGFß-expressing macrophages, and with left-sided primary had higher densities of helper and cytotoxic T cells. In multivariate analysis, high density of M2 macrophages correlated with longer recurrence-free survival (RFS) in the entire cohort [hazard ratio (HR) 0.425, 95% CI 0.219-0.825, p=0.011) and in patients without preoperative chemotherapy (HR 0.45, 95% CI 0.221-0.932, p=0.032). High pSMAD3-expressing macrophages were associated with shorter RFS in CLM after preoperative chemotherapy. Conclusions: Our results highlight the significance of a multi-marker approach to define the macrophage subtypes and identify M2 macrophages as a predictor of favorable prognosis in CLM.