This year’s American Association of Cancer Research (AACR) Annual meeting was held in New Orleans, USA from April 8 to 13. The event was the first Annual Meeting held in-person after 2019. Due to governmental and travel restriction, there was also a possibility to attend online and listen to streamed content via a virtual platform. The content and structure of the Annual Meeting resembled pre-pandemic meetings comprising on lectures, workshops, poster sessions, exhibition and more. In this blog post we concentrate on new preclinical cancer models, and in accordance with a poster that OncoBone presented in the event, work exploring genetic differences in primary tumors and different metastases.
New preclinical models
In any meeting, our interest is to explore new developments in preclinical models. In this meeting, one work that caught our attention was a bone metastasis model induced by caudal artery injection technique (poster number 6010), a method that we have also discussed (Kähkönen et al., 2019). The caudal artery injection technique was first introduced by a Japanese group (Kuchimaru et al., 2018) and it is especially interesting as it allows cancer cells homing to bone from systemic circulation, which is a commonly accepted approach to produce a bone metastasis model. The work presented in AACR reported establishment of two breast cancer models with exclusive metastasis in the hind limbs in tibia and femur.
The interest in humanized mouse models as a choice of IO models is increasing. A new humanized mouse model defective for mouse FcεRI and FcγIIb genes was introduced (poster number 6026). The mice lacked expression of functional mouse FcγRs and activity of endogenous antibody-dependent cellular cytotoxicity (ADCC). When these mice were engrafted with human hematopoietic stem cells (HSCs) it resulted in higher reconstitution of human immune cells, especially CD19+ B-cells and CD33+ myeloid cells than in other mouse strains used in humanizations. The new humanized mouse model also had increased number of activated T cells and memory T cells. This model could induce tumor growth suppression and rejection caused by IO treatment better than traditional humanized mouse strains.
Humanized PDX models are increasingly used in IO research. One study (poster number 6258) compared gene ontology in humanized and immunodeficient TNBC models, demonstrating that biological processes, cellular components, molecular functions and ribosomal relevant proteins, but not immune related genes, were more upregulated in the humanized TNBC PDX model than in the immunodeficient model.
Bone marrow immune microenvironment contributes to dormancy and activation of disseminated tumor cells (DTCs) in bone metastasis. One study (poster number 5985) compared bone marrow samples from mice with and without bone metastases and intact animals. Mice with bone metastases had lower number of T and B cells in the bone marrow than intact mice, indicating that acquired immunity was diminished in the mice with bone metastases. This also aligns with results we have previously reported in AACR Annual meeting, showing a very low number of T cells in bone metastatic tumor microenvironment (Kähkönen et al., 2018). An increased number of immunosuppressive cells was also observed in the bone marrow of mice with bone metastases, leading to development of immunosuppressive microenvironment, promoting growth of bone metastases.
In summary, new developments in oncology drug discovery and development create a need for more predictive preclinical models for supporting the activities. There have been two important advancements in this area, development of models that recapitulate the disease progression and metastasis, and more advanced immunocompetent models with more complete functional human immune system. These advancements substantially increase clinical predictivity of preclinical work.
Genetic profiles in primary tumor and different metastasis
In AACR Annual meeting, OncoBone presented a poster titled: “Identification of genetic signatures in bone metastasis of breast and prostate cancer”. The work summarizes novel genetic changes expressed in bone metastasis of breast and prostate cancer. The data was obtained from a dataset of 500 metastatic solid tumors, including metastasis-specific biopsy data (Robinson et al., 2017). Genetic alterations in bone metastasis and in other than bone metastasis were compared to identify genetic alterations that would be increasingly or exclusively expressed in bone metastasis. The study identified 8 genes in breast cancer and 3 genes in prostate cancer that were significantly different between the cohorts. Of these, 4 genetic alterations in breast cancer and 1 in prostate cancer showed a significant difference on patient survival in larger cohorts.
Also, other studies presented in AACR underlined the genetic difference in primary tumors and metastases. One study (poster number 5983) reported differences in breast cancer and related lung, liver and brain metastases. High tumor heterogeneity was observed between samples and between different metastases. The five most mutated genes were mostly different in primary tumors and metastases, with some exceptions such as TP53 that was mutated in all samples. Lung and brain metastases were most different from primary tumor. Tumor mutational burden (TMB) was highly different between the primary tumors and metastases.
One study (poster number 5134) reported differences between matched primary and metastatic colorectal tumors. The most common site of metastasis was liver (about 70%) followed by low rates of ovarian and peritoneal metastases. There was a high concordance in the mutational landscape and 80% of the 20 most commonly observed genes were shared between the primary and metastatic tumors. There was also a high heterogeneity between the samples, and some metastatic locations seemed to harbor mutations that were not observed in the primary tumor or in other metastatic locations. TMB was comparable between primary tumor and metastatic locations.
In summary, it is great to note that understanding genetic drivers of metastasis has aroused interest in the cancer research society. Based on the studies presented in AACR, it seems obvious that genetic drivers can be different in metastasis, and the metastatic location can strongly affect TMB and increase the heterogeneity in genetic landscape. The more different the metastatic location is from the primary tumor, the more complex these changes seem to be.
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